@article{3b4ac1dd85014e60b0ff5cfb608f1622,
title = "Priming of microglia in a DNA-repair deficient model of accelerated aging",
abstract = "Aging is associated with reduced function, degenerative changes, and increased neuroinflammation of the central nervous system (CNS). Increasing evidence suggests that changes in microglia cells contribute to the age-related deterioration of the CNS. The most prominent age-related change of microglia is enhanced sensitivity to inflammatory stimuli, referred to as priming. It is unclear if priming is due to intrinsic microglia ageing or induced by the ageing neural environment. We have studied this in Ercc1 mutant mice, a DNA repair-deficient mouse model that displays features of accelerated aging in multiple tissues including the CNS. In Ercc1 mutant mice, microglia showed hallmark features of priming such as an exaggerated response to peripheral lipopolysaccharide exposure in terms of cytokine expression and phagocytosis. Specific targeting of the Ercc1 deletion to forebrain neurons resulted in a progressive priming response in microglia exemplified by phenotypic alterations. Summarizing, these data show that neuronal genotoxic stress is sufficient to switch microglia from a resting to a primed state.",
keywords = "Aging, DNA damage, Hyperactivation, Microglia, Neuroinflammation, Neuron-glia interaction, Phagocytosis, Priming",
author = "Raj, {Divya D.A.} and Dick Jaarsma and Holtman, {Inge R.} and Marta Olah and Ferreira, {Filipa M.} and Wandert Schaafsma and Nieske Brouwer and Meijer, {Michel M.} and {De Waard}, {Monique C.} and {Van der Pluijm}, Ingrid and Renata Brandt and Kreft, {Karim L.} and Laman, {Jon D.} and {De Haan}, Gerald and Biber, {Knut P.H.} and Hoeijmakers, {Jan H.J.} and Eggen, {Bart J.L.} and Boddeke, {Hendrikus W.G.M.}",
note = "Funding Information: Part of the work has been performed at the UMCG microscopy and imaging center (UMIC), which is sponsored by NWO -grants 40-00506-98-9021 and 175-010-2009-023 . Help with live imaging by Klaas Sjollema (UMCG) and Gert van Cappellen (Erasmus MC) is greatly acknowledged. Operators of central FACS facility of UMCG, Geert Mesander and Henk Moes are acknowledged. The authors also acknowledge advice with statistical methods by Ilia Vainchtein. This work was supported by the European commission FP7 Markage ( FP7-Health-2008–200880 ), National Institute of Health (NIH)/National Institute of Aging (NIA) ( 1PO1 AG-17242-02 ), NIEHS ( 1UO1 ES011044 ), and the Royal Academy of Arts and Sciences of the Netherlands (academia professorship to Jan H.J. Hoeijmakers) and a European Research Council Advanced Grant to Jan H.J. Hoeijmakers. The research leading to these results has received funding from the European Community's Seventh Framework Programme (FP7/2007–2013) under grant agreement No. HEALTH-F2-2010- 259893 . This work was also supported by the Mouse Clinic for Cancer and Aging through a RoadMap grant from the Netherlands Organization for Scientific Research (NWO) . The MSCenter ErasMS is supported by a program grant of the Dutch MS Research Foundation. ",
year = "2014",
month = sep,
doi = "10.1016/j.neurobiolaging.2014.03.025",
language = "English",
volume = "35",
pages = "2147--2160",
journal = "Neurobiology of Aging",
issn = "0197-4580",
publisher = "Elsevier Inc.",
number = "9",
}